One pathogenetic cause of hypertension and coronary cerebral circulatory disturbances (e.g., angina pectoris, cerebral infarction and the like) which pose serious social problems as adult diseases is considered to be an abnormal contraction of smooth muscle. The contraction and relaxation of smooth muscle are mainly controlled by increase and decrease of intracellular calcium. The calcium which has flowed into smooth muscle cells binds with calmodulin to activate myosin light chain phosphorylation enzyme. As a result, myosin light chain is phosphorylated to cause contraction of smooth muscles (myosin phosphorylation theory). Taking note of this theory, various calcium antagonists have been developed which reduce intracellular calcium and distend blood vessels, and widely used for the therapy of hypertension, angina pectoris and the like.
Inasmuch as a sustained contraction of smooth muscle of blood vessel, trachea and the like, which is characteristic of smooth muscle, is inexplicable by myosin phosphorylation theory alone, an involvement of contraction mechanism which is independent of intracellular calcium level, and calcium sensitivity reinforcing mechanism, have been suggested in recent years. Such involvement is supported by the occurrence of contraction of smooth muscle and diseases (e.g., cerebral vasospasm, asthma and the like) on which calcium antagonists are ineffective. Therefore, a pharmaceutical agent which only reduces intracellular calcium is insufficient to treat diseases caused by contraction of smooth muscle, and the development of a new smooth muscle relaxant has been awaited.
Benzamide compounds as cardiotonics have been reported in Japanese Patent Unexamined Publication Nos. 158252/1987 and 158253/1987; as antiulcer agents in J. Med. Chem., 14, 963 (1971); and as intestinal peristaltic movement inhibitors in Spanish patent No. 456,989. Yet, no reports have documented their smooth muscle relaxing action.
On the other hand, WO 93/05021 discloses that 4-amino(alkyl)-cyclohexane-1-carboxamide compounds are useful as potent and longacting anti-hypertensive agents, agents for prevention and treatment of circulatory diseases of coronary, cerebral, renal and peripheral arteries, and therapeutic agents for asthma.
It is therefore an object of the present invention to provide an agent which can be administered orally, which has strong smooth muscle relaxing action, hypotensive action and cerebral coronary vasodilating action like conventional calcium antagonists, as well as sustained renal and peripheral circulation improving action, and which also suppresses, unlike calcium antagonists, vasoconstriction caused by various agonists.